Cerebral deposition of -amyloid peptides (A) is a pathological hallmark of Alzheimer's disease (AD). A is generated by sequential proteolysis of -amyloid precursor protein (APP) by the -secretase and ?-secretase complexes. Although APP plays a central role in AD pathogenesis, its physiological functions remain largely undefined. Recently several reports suggest that APP can regulate both anterograde and retrograde axonal transport. In preliminary studies we demonstrate that APP regulates intracellular trafficking of presenilin 1 (PS1), a critical component of the ?-secretase complex. In addition, cell surface levels of three other ?- secretase complex components, nicastrin, APH-1 and PEN-2, and the two nerve growth factor receptors, TrkA and p75NTR, are also regulated by APP. Together these data suggest that APP regulates intracellular trafficking of specific membrane proteins, which is the central hypothesis in this proposal. Moreover, our results suggest that multiple cytosolic factors may function in APP-regulated protein trafficking. The interplay between APP, cytosolic factors and target proteins through intracellular trafficking pathways (both secretory and endocytic) is crucial for cells to function normally, and disturbing this interplay may cause disease pathogenesis, including AD. We propose to use biochemical, molecular and cell biology techniques to accomplish the following specific aims: Aim 1. To demonstrate the role of APP in regulating the trafficking of several membrane proteins crucial for AD pathogenesis and neuronal functions/survival. Aim 2. To determine the cellular mechanisms (e.g., the involvement of cytosolic factors) by which APP regulates trafficking of PS1/?-secretase and other proteins. Aim 3. To investigate the effects of trafficking regulation of PS1/?-secretase and other membrane proteins on PS1/?-secretase actions and neuronal activities, such as neurite outgrowth and synaptic activity. Successful completion of this proposal will shed light on our understanding of physiological functions of the highly important APP molecule. PUBLIC HEALTH RELEVANCE: Alzheimer's disease (AD) is a prevalent aging-associated disorder afflicting millions of elderly individuals worldwide. Its exact causes remain elusive, and there is no cure for AD. Although -amyloid precursor protein (APP) plays a central role in AD pathogenesis, the physiological functions of APP are largely undetermined. We will elucidate one important physiological function of APP as a protein trafficking regulator whose targets include PS1/secretase, -secretase and nerve growth factor receptors TrkA/p75NTR. Results of these studies will greatly facilitate our understanding of AD pathogenesis and aid in the development of therapeutics.